Assessing the role of rare pathogenic variants in heart failure progression by exome sequencing in 8,089 patients

Most therapeutic development is targeted at slowing disease progression, often long after the initiating events of disease incidence. Heart failure is a chronic, life-threatening disease and the most common reason for hospital admission in people over 65 years of age. Genetic factors that influence heart failure progression have not yet been identified. We performed an exome-wide association study in 8,089 patients with heart failure across two clinical trials, CHARM and CORONA, and one population-based cohort, the UK Biobank. We assessed the genetic determinants of the outcomes ‘time to cardiovascular death’ and ‘time to cardiovascular death and/or hospitalisation’, identifying seven independent exome-wide-significant associated genes, FAM221A , CUTC , IFIT5 , STIMATE , TAS2R20 , CALB2 and BLK . Leveraging public genomic data resources, transcriptomic and pathway analyses, as well as a machine-learning approach, we annotated and prioritised the identified genes for further target validation experiments. Together, these findings advance our understanding of the molecular underpinnings of heart failure progression and reveal putative new candidate therapeutic targets. ### Competing Interest Statement O.C., Q.W., L.M., D.V., A.W., Q.-D.W., K.M.H., C.H., D.S.P. and K.C. report personal fees from AstraZeneca during the conduct of the study. Q.W., C.H. and D.S.P. are stockholders of AstraZeneca. M.-P.D. reports personal fees and minor equity interest from Dalcor, other from AstraZeneca, GlaxoSmithKline, Pfizer, Servier, Sanofi. J.C.T. reports a grant from AstraZeneca for the conduct of the study; other grants from AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer and RegenXBio; honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Pharmaceuticals, Pendopharm and Pfizer; minor equity interest in DalCor Pharmaceuticals. J.C.T. is author on patents ?Methods of treating a coronavirus infection using Colchicine and Methods of treating a coronavirus infection using Colchicine? pending and a patent ?Early administration of low-dose colchicine after myocardial infarction? pending assigned to the Montreal Heart Institute. M.-P.D. and J.C.T. are authors on a patent ?Methods for Treating or Preventing Cardiovascular Disorders and Lowering Risk of Cardiovascular Events? issued to Dalcor, no royalties received, a patent ?Genetic Markers for Predicting Responsiveness to Therapy with HDL-Raising or HDL Mimicking Agent? issued to Dalcor, no royalties received, and a patent ?Methods for using low dose colchicine after myocardial infarction?, assigned to the Montreal Heart Institute. J.C.T. has waived his rights in colchicine patents and does not stand to gain financially. C.B.G. reports personal fees from AbbVie, Bayer, Boston Scientific, CeleCor, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan and Roche; grants from Akros, Apple, AstraZeneca, Daiichi Sankyo, US Food and Drug Administration, GlaxoSmithKline and Medtronic Foundation; grants and personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis and Pfizer; and other support from Duke Clinical Research Institute outside the submitted work. Funding for the exome sequencing in the CHARM, CORONA and UK Biobank studies was provided fully or partially by AstraZeneca. ### Funding Statement We thank the participants and investigators of the UK Biobank study who made this work possible (Resource Application Number 26041). We thank the UKB Exome Sequencing Consortium (UKB-ESC) members AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen, Bristol-Myers Squibb, Pfizer, Regeneron and Takeda for funding the generation of the data, and the Regeneron Genetics Center for completing the sequencing and initial quality control of the exome sequencing data. We acknowledge the AstraZeneca Centre for Genomics Research Analytics and Informatics team for processing and analysis of sequencing data. We thank all the study participants for contributing to this effort and the CHARM and CORONA co-investigators. Finally, we thank Sri Deevi and Dorota Matelska from the AstraZeneca Centre for Genomics Research for their support, for which we are grateful. M.-P.D. is funded by the Canada Research Chairs Program and by the Health Collaboration Acceleration Fund from the Government of Quebec. J.C.T. holds the Canada Research Chair in personalized and translational medicine and the Université de Montréal endowed research chair in atherosclerosis. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Sites participating in the CHARM and CORONA studies received approval from local ethics committees for their conduct. Only patients who gave written informed consent for genetic analysis and for whom a DNA sample was available were included in the present study. The present study was performed in accordance with the policies on bioethics and human biologic samples of AstraZeneca. The protocols for UK Biobank are overseen by the UK Biobank Ethics Advisory Committee. For more information see https://www.ukbiobank.ac.uk/ethics/. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes